The present invention relates to the field of pharmacology and more particularly, to novel conjugates, pharmaceutical compositions including same and to uses thereof for treating CNS-associated diseases and disorders.
γ-Aminobutyric acid (GABA) is one of the major inhibitory transmitters in the central nervous system of mammals. GABA is not transported efficiently into the brain from the bloodstream because of poor transport properties that prevent passage through the blood-brain barrier. Consequently, brain cells synthesize virtually all of the GABA found in the brain (by decarboxylation of glutamic acid with pyridoxal phosphate).
GABA regulates neuronal excitability through binding to specific membrane proteins (i.e., GABA receptors), which results in opening of an ion channel. The entry of chloride ion through the ion channel leads to hyperpolarization of the recipient cell, which consequently prevents transmission of nerve impulses to other cells. Low levels of GABA have been observed in individuals suffering from epileptic seizures, motion disorders (e.g., Parkinson's disease, Multiple Sclerosis, action tremors, tardive dyskinesia), panic, anxiety, depression, alcoholism and manic behavior. Administering GABA to the brain is therefore expected to improve symptoms of these diseases and disorders.
Unfortunately, the clinical use of GABA for treating CNS-associated diseases or disorders is presently limited since the GABA molecule includes hydrophilic functional groups (e.g., a free carboxylic acid group and a free amino group) and therefore does not readily cross the blood brain barrier (BBB).
Recent studies on extrapyramidal symptoms suggest that GABA may reduce side effects of psychotropic drugs, and particularly side effects induced by neuroleptics. Psychotropic drugs are pharmacological agents which act mainly in the central nervous system (CNS) by modulating neuronal signals transduction. Unfortunately, the administration of psychotropic drugs is often associated with adverse side effects which severely limit their use. A comprehensive list of such side effects can be found, for example, in “The Merck Manual of Medical Information” (Merck & Co. Inc.).
Furthermore, previous studies have suggested that GABA can interfere with other brain neurotransmitters and, in particular, with the dopamine system. Thus, it was found that GABA can antagonize the neuroleptic-induced increase of dopamine receptors sensitivity and is therefore capable of improving neuroleptic-induced dyskinesia (Lloyd et al., Pharmacol. Biochem. Behav. 18: 957-66, 1983).
In addition, it was found that some known direct GABA agonists (e.g., muscimol and SL 76002) cause a biphasic effect on haloperidol-induced catalepsy, such that while low doses of the agonist inhibit the stereotypic catalepsy behavior, high doses of the agonist potentiate the haloperidol-induced catalepsy. Other studies have reported that GABA agonists further induce anti-convulsive activity (Capasso et al., Eur. Neuropsychopharmacol. 7: 57-63, 1997).
Thus, while GABA, as well as other GABA agonists, can serve as highly potent agents for treating, interfering or otherwise beneficially affecting CNS-associated conditions (e.g., by reducing side effects induced by psychotropic drugs), the use of these compounds is limited by their low permeability through the blood brain barrier and hence by poor delivery of such compounds into the brain.
A series of conjugates of psychotropic drugs and GABA and their use in the treatment of psychotic and/or proliferative diseases and disorders are described in detail in International Patent Applications published as WO 03/026563 and WO 2005/092392 and in U.S. Patent Application No. 20040242570, which are all incorporated by reference as if fully set forth herein.
Glycine is another important inhibitory transmitter in the central nervous system of mammals. Similarly to GABA, glycine is not transported efficiently into the brain from the bloodstream since the glycine molecule includes hydrophilic functional groups (a free carboxylic acid group and a free amino group) and therefore does not readily cross the blood-brain barrier (BBB).
Glycine regulates neuronal excitability through binding to strychnine-sensitive and strychnine-insensitive glycine binding sites. The strychnine-insensitive glycine binding site is located on the N-methyl-D-aspartate (NMDA) receptor complex. Glycine binds with high affinity to this site, leading to opening of an ion channel. The entry of chloride ion through the ion channel leads to hyperpolarization of the recipient cell, which consequently prevents transmission of nerve impulses to other cells.
Despite its poor capacity to cross the BBB, glycine in high doses may be beneficial in the management of CNS diseases and disorders.
Accordingly, high-dose glycine supplementation has been shown to improve the “negative symptoms” of schizophrenia (such as “flat” emotional expression, depression, poverty of speech, apathy, and social withdrawal). Glycine also appears to boost the efficacy, and reduce the side-effects, of schizophrenia medications (Heresco-Levy et al., Arch Gen Psychiatry. 56:29-36, 1999; Coyle and Tsai, Psychopharmacology 174:32-38, 2004; Shoham et al., Brain Res. 1004:142-147, 2004).
Glycine has also been shown to reduce convulsive seizures per se (de Kooning et al., Ann. Neurol 44:261-265, 1998; Toth and Lajtha, Neurochem Res. 9:1711-1718, 1984) or to potentiate the efficiency of anti-convulsive drugs (Liu et al., Eur J Pharmacol. 182:109-15, 1990).
In addition, glycine supplementation has been shown to improve learning and cognition in healthy human adults (File et al., J. Clin. Psychopharmacol 19:506-512, 1999).
U.S. Pat. No. 4,639,468 describes the compound 2-N-pentylaminoacetamide (milacemide) which crosses the BBB and acts as a glycine prodrug to deliver glycine to the brain. Milacemide is metabolized by monoamine oxidase B (MAO-B) to glycinamide which in turn is converted to glycine.